1. Technical Field
The present invention relates generally to thrombopoietic compositions comprising tyrosyl-tRNA synthetase polypeptides, including truncations and/or variants thereof, and methods of using such compositions in the treatment of diseases or conditions that benefit from increased thrombopoiesis, such as diseases or conditions associated with thrombocytopenia.
2. Description of the Related Art
Thrombocytopenia relates generally to a condition in which the number of platelets per unit volume of peripheral blood in a subject is lower than normal. For example, normal platelet counts generally range from about 150,000 mm3 to about 450,000 mm3, and thrombocytopenia is typically characterized by a decrease in the platelet count to about 100,000/mm3 or less.
Platelets, or thrombocytes, are colorless blood cells that play an important role in blood clotting by clumping together and forming plugs in blood vessel holes. Thrombopoiesis refers to the process by which platelets are formed from precursor hematopoietic cells, such as megakaryocytes. Thrombopoiesis is primarily regulated by thrombopoietin, which is in turn regulated by a variety of mechanisms, such as receptor-mediated uptake and destruction in response to increased platelet levels, among other factors.
Thrombocytopenia is associated with many underlying causes, such as increased destruction of platelets, decreased production of platelets, consumption of platelets, trapping of platelets, in addition to medication-induced thrombocytopenia. Given the central role of platelets in blood clotting, initial symptoms of thrombocytopenia normally involve various forms of bleeding and purpura. Since subjects are at increased risk for bleeding, early diagnosis and treatment are important, especially for the prevention of progress to more serious symptoms, such as cerebral bleeding.
Treatment for conditions of reduced platelet count is often guided by etiology and disease severity. Currently available treatments for thrombocytopenia and related conditions include, for example, corticosteroids, IVIG, splenectomy, and platelet transfusion, which methods are either palliative and non-specific, or drastic and expensive. In addition, previous efforts to utilize thrombopoietin, the primary biological mediator of thrombopoiesis, have failed in the clinic due to the serious effects observed in patients who developed an immune response to the drug and, consequently, to their own endogenous thrombopoietin. Thrombopoietin mimetics and small molecule activators of the thrombopoietin receptor are in development but have not been approved by the Food and Drug Administration (FDA).
Aminoacyl-tRNA synthetases, which catalyze the aminoacylation of tRNA molecules, are essential for decoding genetic information during the process of translation. In higher eukaryotes, aminoacyl-tRNA synthetases associate with other polypeptides to form supramolecular multienzyme complexes. Each of the eukaryotic tRNA synthetases consists of a core enzyme, which is closely related to the prokaryotic counterpart of the tRNA synthetase, and an additional domain that is appended to the amino-terminal or carboxyl-terminal end of the core enzyme. Human tyrosyl-tRNA synthetase (YRS), for example, has a carboxyl-terminal domain that is not part of prokaryotic and lower eukaryotic YRS molecules.
Aminoacyl tRNA synthetases, such as tyrosyl-tRNA synthetase, are currently associated with expanded functions in mammalian cells, including activities in signal transduction pathways, among others.